Expression of cyclin D2 and D3 in lymphoid lesions

Teramoto, Norihiro; Pokrovskaja, Katja; Szekeres, L.; Polack, Axel; Yoshino, Tadashi; Akagi, Tadaatsu; Klein, George

doi:10.1002/(sici)1097-0215(19990517)81:4<543::aid-ijc7>3.0.co;2-3

Cited by 39 publications

(17 citation statements)

References 21 publications

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“…Of note, prior gene expression profiling studies showed low abundance of cyclin D2 in germinal center B-cells,22 although our data shows variable expression of cyclin D2 protein in germinal center B-cells. Our findings also differ from a previous report that found that cyclin D3 but not cyclin D2 was expressed in germinal center B-cells 30. Whether the differential expression of cyclins D2 and D3 proteins is associated with patient outcome warrants further investigation in a cohort of diffuse large B-cell lymphoma patients uniformly treated with Rituximab-based immunochemotherapy as these regimens have been shown to be of improved benefit in patients with diffuse large B-cell lymphoma 31–34…”

Section: Discussioncontrasting

confidence: 96%

Characterization of D-cyclin proteins in hematolymphoid neoplasms: lack of specificity of cyclin-D2 and D3 expression in lymphoma subtypes

et al. 2010

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D-cyclin proteins play a central role in cell cycle regulation and are involved in the pathogenesis of lymphomas. In mantle cell lymphoma, the t(11;14) translocation leads to the overexpression of cyclin D1, in addition to which cyclin D1-negative mantle cell lymphoma that overexpress cyclin D2 or D3 have also been described. Although cyclins D2 and D3 have been implicated in the prognosis of specific lymphoma subtypes, a thorough characterization of D-cyclin protein expression in human hematolymphoid neoplasia has not been reported. To evaluate the tissue expression patterns of D-cyclins, particularly D2 and D3, in normal and neoplastic hematolymphoid tissues, we optimized commercially available antibodies for D-cyclins for use on paraffin-embedded tissue and stained tissue microarrays of over 700 patient samples. Our results show that cyclin D2 and D3 proteins are expressed in many more lymphoma subtypes than cyclin D1. Cyclins D1, D2 and D3 were expressed in 100%, 22% and 6% of mantle cell lymphoma and 2%, 49% and 20% of diffuse large B-cell lymphoma. Fluorescence in situ hybridization studies confirmed the presence of the CCND1/IGH translocation in the majority of mantle cell lymphoma but not in diffuse large B-cell lymphoma that expressed cyclin D1 protein. In addition, a subset of follicular, marginal zone, lymphoplasmacytic, lymphoblastic, classical Hodgkin, mature T- and Natural Killer cell lymphomas and acute myeloid leukemias also expressed cyclins D2 and D3. These data support the hypothesis that dysregulation of cell cycle control by D-cyclins contribute to the pathogenesis of hematolymphoid neoplasia, and suggest a potential role for these proteins in the prognostic and therapeutic aspects of these diseases. For diagnostic purposes, however, the expression of D-cyclin proteins should be interpreted with caution in the subclassification of lymphoma types.

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Section: Discussioncontrasting

confidence: 96%

Characterization of D-cyclin proteins in hematolymphoid neoplasms: lack of specificity of cyclin-D2 and D3 expression in lymphoma subtypes

et al. 2010

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“…The ability of S75X to interact more efficiently with the CXCR2 receptor, as compared with reference p17, may be, at least partially, responsible for the enhanced growthpromoting properties exerted by this variant protein in primary EBV-infected B-lymphocytes and in the EBV 1 CXCR2 1 HBL-1 lymphoma B-cell line. These effects are probably mediated by up-regulation of cyclin D2 and D3, two main drivers of B-cell proliferation, [23][24][25] occurring at both mRNA and protein levels. Moreover, S75X, but not p17, was able to significantly enhance the production of IL-6 by EBV-infected B-lymphocytes obtained from unrelated donors.…”

Section: Discussionmentioning

confidence: 99%

A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: Implications for EBV-driven lymphomagenesis in the HIV setting

et al. 2015

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Human immunodeficiency virus p17 matrix protein is released by infected cells and may accumulate within lymphoid tissues where it may deregulate the biological activities of different cell populations by binding to CXCR1 and CXCR2 cellular receptors. S75X, a natural p17 variant, was recently shown to enhance the malignant properties of lymphoma cells. We investigated a reference p17 protein and the S75X variant for their ability to bind to Epstein-Barr virus (EBV)-infected primary and fully transformed B-lymphocytes and trigger downstream effects of potential pathogenic relevance. We demonstrate that EBV infection of primary B-lymphocytes or the ectopic expression of the latent membrane protein-1 viral oncoprotein in EBV-negative Bcells up-regulates CXCR2, but not CXCR1. Multispectral imaging flow cytometry showed that EBV-infected primary B-cells more efficiently bind and internalize p17 proteins as compared with activated B-lymphocytes. The S75X variant bound more efficiently to EBV-infected primary and fully transformed B-lymphocytes compared with reference p17, because of a higher affinity to CXCR2, and enhanced the proliferation of these cells, an effect associated with cyclin D2 and D3 up-regulation and increased interleukin-6 production. Notably, the S75X variant markedly up-regulated latent membrane protein-1 expression at both mRNA and protein levels and enhanced the activation of Akt, ERK1/2 and STAT3 signaling, thereby contributing to EBV 1 B-cell growth promotion. These results indicate that EBV infection sensitizes B-lymphocytes to CXCR2-mediated effects of p17 proteins and provide evidence supporting a possible contribution of natural p17 variants to EBV-driven lymphomagenesis in the human immunodeficiency virus setting.

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“…It is highly expressed in proliferating lymphocytes, either in germinal centers or extrafollicular areas [159][160][161]. A few studies point to a possible oncogenic role of cyclin D3 in lymphomagenesis.…”

Section: Cellular Origin Of Human B Cell Lymphomamentioning

confidence: 99%

“…A few studies point to a possible oncogenic role of cyclin D3 in lymphomagenesis. Immunohistochemical analysis of lymphoma tissues showed high levels of cyclin D3 were expressed in a number of aggressive DLBLs, more frequently in BLs [159] and in certain high grade FLs and HDs [160]. A recent study revealed that the high level of cyclin D3 expression in DLBCLs was associated with poor clinical outcome [162].…”

Section: Cellular Origin Of Human B Cell Lymphomamentioning

confidence: 99%

“…Genomic rearrangements that lead to the truncation of the NF-κB2 protein and its translocation into a constitutive transcriptional activator have been reported in some DLBCLs [222,223]. MALT lymphomas frequently present with a translocation t(11;18) that induces overexpression of MALT1 [160,224], which is an activator of NF-κB [225,226]. Bcl-10, a MALT1-interacting protein that is required for the activation of NF-κB downstream of antigen receptor signaling [227], has also been overexpressed in some of these lymphomas due to translocations involving Bcl-10 and IgH loci [228].…”

Section: Blocking Apoptosismentioning

confidence: 99%

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Lymphoma and the Control of B Cell Growth and Differentiation

Goodnow²

2006

CMM

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It is now widely accepted that lymphomagenesis is a multistep transformation process. A number of genetic changes and environmental and infectious factors contributing to the development and malignant progression of B-cell lymphoproliferative disorders are well documented. Reciprocal chromosomal translocations involving the immunoglobulin loci are a hallmark of most mature B cell lymphomas and lead to dysregulated expression of proto-oncogenes (c-myc) important for cell proliferation or genes involved in cell cycle progression (cyclin D1), differentiation block (bcl-6, PAX5) and cell survival (bcl-2, NF-kappaB). In addition, genetic alterations that inactivate tumor suppressor genes (p53, p16) have been frequently detected in some lymphoma tissues. Many of these genes are normally regulated by signals from the B cell antigen receptor. The high prevalence of bacterial and viral infection in lymphoma patients supports the hypothesis that infectious agents may play a contributory role in the development and evolution of B cell lymphoproliferative disorders by either directly inducing polyclonal B cell hyperactivation (EBV, HCV), or providing a chronic antigenic stimulus (EBV, HCV, HBV, H. pylori), or mimicking B cell antigen receptor signaling (EBV, HCV, HHV8), although whether these are causative factors or they are secondary to genetic changes in lymphomagenesis remains to be defined. Stimulatory signals from reactive T cells, local cytokines and growth factors can also contribute, to some extent, to the progression of transformation. Modulation of B cell antigen receptor signaling therefore emerges as a potentially powerful strategy for controlling the growth of certain B cell lymphomas.

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Expression of cyclin D2 and D3 in lymphoid lesions

Cited by 39 publications

References 21 publications

Characterization of D-cyclin proteins in hematolymphoid neoplasms: lack of specificity of cyclin-D2 and D3 expression in lymphoma subtypes

Characterization of D-cyclin proteins in hematolymphoid neoplasms: lack of specificity of cyclin-D2 and D3 expression in lymphoma subtypes

A natural HIV p17 protein variant up-regulates the LMP-1 EBV oncoprotein and promotes the growth of EBV-infected B-lymphocytes: Implications for EBV-driven lymphomagenesis in the HIV setting

Lymphoma and the Control of B Cell Growth and Differentiation

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